Cyclin D1-specific cytotoxic T lymphocytes are present in the repertoire of cancer patients: implications for cancer immunotherapy.
OBJECTIVE
Cyclin D1, a key cell cycle regulator, is overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for cancer immunotherapy. Nevertheless, it had previously been suggested that efficient T cells recognizing cyclin D1-derived epitopes are absent from the repertoire because of thymic deletion. We attempted to induce autologous CTL from healthy donors and patients with cyclin D1-overexpressing tumors using a highly efficient T-cell expansion system based on CD40-activated B cells as antigen-presenting cells.


METHODS
Cyclin D1-derived, HLA-A*0201-restricted epitopes were predicted by multiple computer algorithms, screened in HLA-A2-binding assays, and used for T-cell stimulation. The generated CTL lines and clones were analyzed by IFN-gamma enzyme-linked immunosorbent spot assay or cytolysis assay.


RESULTS
After screening, at least two naturally processed and presented HLA-A*0201-binding cyclin D1 epitopes were identified. CTL specific for these epitopes could be successfully generated from HLA-A2(+) donors. T cells efficiently recognized target cells pulsed with the cognate peptide and cyclin D1-expressing tumor cell lines in an HLA-A*0201-restricted manner. More importantly, HLA-A*0201-matched, primary cyclin D1(+) tumor cells were efficiently recognized by cyclin D1-specific CTL. These CTL could be generated from patients with mantle cell lymphoma and cyclin D1(+) colon cancer.


CONCLUSIONS
These results underscore that cyclin D1 needs to be considered as a target for broad-based antitumor immunotherapy.
Kondo
Eisei
E
1st Department of Internal Medicine, Max-Eder-Nachwuchsgruppe der Deutschen Krebshilfe, University Hospital of Cologne, Cologne, Germany.
Maecker
Britta
B
Weihrauch
Martin R
MR
Wickenhauser
Claudia
C
Zeng
Wanyong
W
Nadler
Lee M
LM
Schultze
Joachim L
JL
von Bergwelt-Baildon
Michael S
MS
D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy; D019938:Cyclin D1 / Q000276:immunology*; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000276:immunology* / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
C530104:CCND1 protein, human; D019013:CD40 Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D019938:Cyclin D1; D007371:Interferon-gamma